tbuckley/cabot-search huggingface dataset:
QOL-17. UNDERSTANDING MULTIDISCIPLINARY PROVIDER PERSPECTIVES AND PREFERENCES FOR INCORPORATING EXERCISE INTO PRIMARY BRAIN TUMOR MANAGEMENT
Authors: Shannon Fogh, Yanel Hernandez, Vardhaan Ambati, Sophia Collis, Michael Tawil, Lucy Zhang, Alexa Greenstein, Regan Frederic, Mary Destri, Naomi Hoffer, Kavita Mishra, Natalie Marshall, Susan M Chang, Jennie Taylor
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Exercise has proven benefit in patients with cancer with most studies focused on patients with high functional and neurocognitive status. Patients with brain tumors, however, frequently have deficits in cognition, motor, balance, or other symptoms that are further exacerbated by surgery and adjuvant treatment. We sought to determine providers’ knowledge, attitudes, motivating factors and preferences for integrating exercise into the treatment of patients with brain tumors. METHODS We surveyed multidisciplinary providers in Neurosurgery, Radiation Oncology and Neuro-Oncology from a single, quaternary medical center. Questions assessed demographics, current practices, attitudes, knowledge, motivating factors and barriers for integrating exercise into treatment. Questions were extrapolated from existing published questionnaires and sent electronically. RESULTS Most providers (92%) reported that exercise was important for patients' lifestyle and 80% felt it should be integrated into the treatment of patients with primary brain tumors. Nighty-six percent felt that exercise improved quality of life, decreased fatigue (100%) and reduced treatment related side effects (92%) yet only 57% of providers initiated a conversation about exercise with patients. Top motivating factors for promoting exercise were perceived benefit to patients’ quality of life and disease outcomes. Barriers to provider/patient discussions about exercise included, lack of time or appropriate expertise to discuss exercise with patients, and concern that patients have competing priorities. Some providers (23%) were concerned about potential limitations/complications with patients exercising including inability to participate from side effects of treatment (38%), physical deficits (61%) and fatigue (42%). CONCLUSION Understanding barriers for providers to incorporate exercise into their patients’ treatment regimens is critical to strategizing best practices. Findings from this study help to expand our understanding of barriers and facilitators to incorporating exercise interventions into brain cancer treatment and will assist with the implementation of a structured exercise program to enhance physical health for our patients.
TMIC-62. INHIBITION OF TUMOR-ASSOCIATED COL1A1 MATRIX ARRESTS GLIOMA MESENCHYMAL TRANSFORMATION AND REPROGRAMS THE TUMOR MICROENVIRONMENT
Authors: Andrea Comba, Syed M Faisal, Maria Luisa Varela, Anna Argento, Patrick Dunn, Clifford Abel, Todd Hollon, Wajd Al-Holou, Daniel Zamler, Gunnar Quass, Pierre Apostolides, Phillip Kish, Jacqueline Perelman, Nicole Jacobs, Alon Kahana, Christine Brown, Celina Kleer, Sebastien Motsch, Maria Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2022)

Abstract Tumor mesenchymal transformation (MT) is a hallmark of high-grade gliomas. The mesenchymal state is associated with specific changes related to cell adhesion, migration, and the extracellular matrix. Collagen 1a1 (COL1A1) is a main component of the extracellular matrix in gliomas, and its expression correlates inversely with patient survival. However, the cellular and molecular mechanisms of the tumor-associated COL1A1 matrix in gliomas remains elusive. Our study integrates histopathological features, spatially resolved transcriptomics, cellular dynamics and microenvironment alterations associated with MT in high-grade gliomas. Using deep learning analysis of mouse and human glioma histological samples we identified that the density of areas of MT, named oncostreams, correlates with tumor aggressiveness. Spatial transcriptomics analysis, using laser capture microdissection, identified a signature enriched in extracellular matrix related proteins, in which COL1A1 appeared as a key determinant of mesenchymal organization. Correspondingly, human and mouse high-grade gliomas showed prominent alignment of collagen fibers along these mesenchymal fascicles and higher COL1A1 expression compared to low-grade gliomas. Moreover, RNA fluorescent multiplex assays identified at single cell level that different cells within glioma tumors contribute to COL1A1 expression, including neoplastic cells and perivascular non-neoplastic cells such as ACTA2+, CYR61+ and FAP+. Inhibition of COL1A1 using genetically engineered mouse models decreased areas of mesenchymal transformation and increased survival. COL1A1 downregulation impaired tumor cell proliferation and remodeled the tumor microenvironment by reducing CD68+ macrophages/microglia cells, CD31+ endothelial cells, ACTA2+, CYR61+ and FAP+ perivascular cells, and increased GFAP+ astrocytes infiltration withing the tumor mass. Further studies, using ex-vivo glioma explants demonstrated that CO1A1 downregulation decreased collective invasion of the normal brain, supporting its importance in tumor progression. We propose that COL1A1 expression is a valuable marker for diagnosis, and COL1A1 depletion within glioma tumors is a promising direct or complementary therapeutic approach to reprogram mesenchymal transformation, and halt tumor growth.
MODL-38. DEVELOPMENTAL EFFECTS OF MYBL1 ACTIVATION ON MURINE BRAIN AND GLIAL DEVELOPMENT
Authors: Narmen Azazmeh, Cecile Rouleau, Kate Schoolcraft, Etai Jacob, Seth Malinowski, John P Busanovich, Lori Ramkissoon, Yun Jee Kang, Shakti Ramkissoon, Kristine Pelton, Alice Meng, Victor Jones, Rodderick Bronson, Federica Piccioni, Claudia Kleinman, Pratiti Bandopadhayay, Keith Ligon, Rameen Beroukhim
Journal: Neuro-Oncology (2022)

Abstract Low-grade gliomas (LGG) represent 30% of pediatric brain tumors. Their cellular origins are unknown but are presumed to arise from subtle alterations of progenitor cell cycle regulation during brain development. Rearrangements activating MYB and MYBL1 have been identified as drivers of LGG in angiocentric glioma and diffuse astrocytomas, respectively, but the roles of these genes in the normal brain and the development of LGG are poorly understood. We first performed a developmental analysis of human and mouse Mybl1 expression from bulk and single-cell RNA-sequencing and identified exclusive expression of MYBL1 in neural stem and progenitor cells in the ganglionic eminence. We also found that MYBL1high cell transcriptomes are enriched in genes functionally involved in centromere and mitotic processes, strongly suggesting an association between MYBL1 expression and cellular proliferation states. We next hypothesized that C-terminal truncation may drive tumorigenesis through a direct increase in MYBL1 expression and cell proliferation. We developed a novel Cre-dependent knock-in mouse-model for human truncated MYBL1 expression and tested effects in oligodendroglial(Olig2-cre), astrocytic hGFAP-cre), and somatic(Ubiquitin-cre) cell types. In Ubq-cre:R26-MYBL1-tr mice there was expression and dysplasia in the salivary gland but no significant effects on brain development. In Olig2-Cre+/tg:R26-MYBL1-tr+/fl mice we observed higher susceptibility to motor seizures, early postnatal death without gross or microscopic abnormalities of brain morphology. In contrast, expression in stem cells and astrocytes of hGFAP-Cre+/tg:R26-MYBL1-tr+/flmice drove dramatic abnormalities in brain development and altered proliferation of progenitor and stem cells, but not glioma formation. Single-cell RNA sequencing of MYBL1-tr cells from mNSCs and brains of mice were also used to determine patterns of altered expression driven by MYBL1-tr. These results indicate that aberrant MYBL1 activation affects neural stem/progenitor cell and brain development through altered cell proliferation. Future targeting of the pathways identified may be therapeutically beneficial for patients with LGG driven by MYB-family oncogenes.
TMET-16. DIRECT DETECTION OF 2HG AND GLUTAMATE PRODUCTION USING HYPERPOLARIZED [1-13C-5-12C]-Α-KETOGLUTARATE IN CELL AND IN VIVO GLIOMA MODELS
Authors: Donghyun Hong, Yaewon Kim, Chandrasekhar Mushti, Noriaki Minami, Anne Marie Gillepspie, Georgios Batsios, Celine Taglang, Murali Cherukuri, Jing Wu, Pavithra Viswanath, Rolf Swenson, Daniel Vigneron, Sabrina Ronen
Journal: Neuro-Oncology (2022)

Abstract Mutant IDH leads to 2HG production, which drives glioma development. 13C MRS monitoring of hyperpolarized [1-13C]α-ketoglutarate (αKG) metabolism to 2HG and glutamate provides a non-invasive assessment of the IDH mutation and normal metabolism, respectively. However, monitoring 2HG production in vivo has been challenging because its resonance is within 0.1 ppm of the natural abundance [5-13C]αKG signal of the [1-13C]αKG substrate. Here, we utilized [1-13C -5-12C]αKG, which eliminated the [5-13C]αKG peak. This new approach, combined with an optimized sequence, made it possible to readily monitor the production of both 2HG and glutamate in cells and in vivo in healthy rats or rats with orthotopic patient-derived glioma. Hyperpolarized [1-13C -5-12C]αKG was injected into genetically engineered NHAIDHmut cell lysates, healthy rats, and rats implanted orthotopically with BT257 cells intravenously. 1-D dynamic 13C MRS spectra from cells and in vivo slab spectroscopy data were then acquired using an 11.7 T NMR system and a 3 T pre-clinical scanner, respectively. Injection of the hyperpolarized [1-13C -5-12C]αKG into cell lysates showed clearly detectable dynamic conversion of hyperpolarized [1-13C-5-12C]αKG to 2HG and glutamate. The normal brain showed clear production of glutamate but no 2HG was detected. In tumor-bearing rats, we were able to clearly detect the dynamic production of both 2HG and glutamate. This study demonstrated the utility of hyperpolarized [1-13C-5-12C]αKG as a substrate to clearly assess 2HG production without the confounding presence of the natural abundance peak which cannot be distinguished from 2HG in vivo. Importantly, the detection of 2HG provides a clear indicator of the IDH mutation within the tumor.
TMIC-02. PRE-SURGICAL IMMUNE CHECKPOINT BLOCKADE RESHAPES THE IMMUNE LANDSCAPE AND SPATIAL ARCHITECTURE OF METASTATIC BRAIN TUMORS
Authors: Lu Sun, Jenny Kienzler, Jeremy Reynoso, Alexander Lee, Geoffrey Owens, Richard G Everson, David Nathanson, Timothy Cloughesy, Linda M Liau, Willy Hugo, Won Kim, Robert Prins
Journal: Neuro-Oncology (2022)

Abstract Brain tumors reside in a modified microenvironment where inflammatory processes are heavily regulated. Nevertheless, our recent study showed a significant immune infiltration in recurrent glioblastoma (rGBM) treated with neoadjuvant PD-1 checkpoint blockade therapy. In comparison to GBM, the intracranial response of brain metastases (BrM) to immunotherapy has been less well studied. To test this question, we investigated the effect of pre-surgical immune checkpoint blockade (ICB) on the immune compartments of BrM, using multiplex immunofluorescence, single-cell RNA sequencing and spatial transcriptomics on a total of 17 patients. We found that ICB naïve BrM featured an immune exclusion phenotype with accumulation of immune cells in the fibrovascular stroma, necrotic and hemorrhagic peritumoral areas. Following ICB treatment, T cells and monocyte-derived macrophages were then observed within the tumor parenchyma. Computational receptor-ligand analysis suggested that the tumor-infiltrating T cells and macrophages were highly engaged by checkpoint receptor-ligand pairing, which may drive the T cells into an advanced exhausted state. To further explore the organization and interactions between the immune, stroma and tumor cells in BrM, we utilized the sequencing-based spatial transcriptomics technology. Our spatial transcriptomics data further highlighted the distinct spatial architectures between ICB naïve and –treated BrM tumors. It also pinpointed a unique macrophage subset that are preferentially co-localized with the brain vasculature cells and confined the immune infiltrates to the perivascular space. In summary, our study revealed ICB-induced marked changes in the immune composition and spatial organization in BrM and offers insights into new combination therapies that can help improve the clinical efficacy of immunotherapy for BrM patients.
MODL-20. REDUCTION OR LOSS OF MSH6 CONFERS RESISTANCE TO TEMOZOLOMIDE IN GLIOBLASTOMA
Authors: Montserrat Puigdelloses Vallcorba, Gonzalo Pinero, Dolores Hambardzumyan
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The only intervention that has improved the survival rate of GBM patients over the past several decades has been combining temozolomide (TMZ) with radiotherapy (RT), which increased median survival by only ~2.5 months to where it currently stands at ~15 months. Unfortunately, all GBM patients eventually die due to tumor recurrence. Intrinsic or acquired resistance to TMZ is a significant contributing factor to tumor progression, and various mechanisms have been suggested, including deficiencies in DNA mismatch repair (MMR) genes such as MSH6. To test the biological significance of Msh6 in GBM growth and resistance to TMZ and immunotherapy, we have generated immunocompetent genetically engineered mouse models (GEMMs) of GBM with germline loss of Msh6. To generate tumors with reduced or abrogated Msh6, we utilized GEMMs based on the RCAS/tv-a gene transfer system in combination with mice that exhibited heterozygous and homozygous loss of Msh6. When PDGFB was overexpressed in combination with the silencing of Tp53 to induce tumors, tumor-bearing mice with reduced or deficient Msh6 demonstrated increased tumor growth and shorter survival time compared to wild-type tumor-bearing mice. Our data demonstrate that two weeks of TMZ treatment at a clinically relevant dose of 25 mg/kg provides a significant survival advantage in WT-tumor-bearing mice, while no efficacy was observed in tumor-bearing mice with either heterozygous or homozygous loss of Msh6. We are currently evaluating the mechanism by which of Msh6 confers TMZ-resistance.
NCOG-07. SURVIVAL BENEFIT OF RADIOTHERAPY AND SURGERY IN PATIENTS WITH LUNG CANCER BRAIN METASTASES WITH POOR PROGNOSIS FACTORS: A SINGLE-CENTER, RETROSPECTIVE, PROPENSITY SCORE MATCHING ANALYSIS
Authors: Lun Liang, Zhenning Wang, Hao Duan, Jie Lu, Xiaobing Jiang, Run Cui, Chang Li, Sheng Zhong, Xiaoyu Guo, Hongrong Hu, Zhenqiang He, Likun Chen, Yonggao Mou
Journal: Neuro-Oncology (2022)

Abstract PURPOSE To investigate the effect of radiotherapy and surgery in patients with lung cancer brain metastases (BMs) with poor prognosis factors. METHODS We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. RESULTS Age ≥ 65 years, Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥ 65 years and pretreatment KPS score ≤ 70 before and after PSM. Before PSM,whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in non-surgery patients. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. CONCLUSIONS Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.
MODL-26. EVOLUTION OF MULTI-FACETED GLIOBLASTOMA MICROENVIRONMENTS IN 3D
Authors: Jessica Senior, Amanda Dalby, Joao Correia, Jeremy Pike, Kayley Jaworska, Steve Thomas, Alan Smith, Anke Brüning-Richardson
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas (GBM) account for poor prognosis and dismal survival rates in patients due to their highly aggressive infiltrative nature to rapidly migrate within the brain. Experimental treatments for GBMs using animal models often elicit severe side effects and there are major doubts regarding the usefulness of such in vivo models when undergoing animal to human clinical translation. Here, we describe the development of a series of 3D bioengineered GBM models towards the generation of a more physiologically representative system in which candidate drugs can be tested. Glioma cell lines U87 and U251 derived from human GBM were used along with associated knockdowns of previously described anti-migratory and pro-migratory genes or anti-migratory inhibitors to examine their roles in the actin polymerization pathway in cancer cell migration. GBM models were fabricated by implantation of spheroids within hydrogel microenvironments that were fashioned to exhibit migratory collagen tracts within a non-cell adhesive outer shell. The distribution of collagen was organised to have low, intermediate, and high-density regions within the construct, replicating the complexity of native GBM. 3D models were then cultured under control conditions (media only) or treated with anti-migratory drugs (CCG-1423, rhosin or combination). Using light-sheet and confocal microscopy, migration velocity, cell phenotype and migratory behaviours were analysed in live and fixed tumour mimics. In models where migration is promoted, actin was vastly upregulated and cells assumed a migratory mesenchymal phenotype, whereas under anti-migratory drug treatment, cells were amoeboid in shape with a dramatic reduction in actin expression and consequently limited migration velocity. Here, we have demonstrated that it is possible to develop biologically-relevant GBM models that capture the anisotropic nature of the tumour microenvironment using multi-layer biopolymer engineering. The ultimate goal of this research is to develop technology that can help provide personalised treatments for GBM and subsequently improve patient outcomes.
NCOG-43. A RETROSPECTIVE ANALYSIS OF THE IMPACT OF THE COVID-19 INFECTION ON NEURO-ONCOLOGY CARE AND PATIENT OUTCOMES: A TWO-SITE STUDY
Authors: Margaret Johnson, Jennifer Durling, Casey B Brown, Mustafa Khasraw, Zoey Petitt, Nicole Cort, Eric S Lipp, Evan D Buckley, James E Herndon, Waynekid Kam, Karen Gao, Milan G Chheda, Omar H Butt
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND COVID-19 radically changed neuro-oncology care. In this retrospective study, we examine the impact of COVID-19 infection on neuro-oncological care and clinical outcomes in two geographically separate populations. METHODS Descriptive statistics compared demographic and clinical history extracted from the medical records of COVID-19 positive patients with primary brain tumors treated between 3/1/2020 and 3/31/2021. All subjects were unvaccinated given our cohort pre-dates the ubiquitous availability of vaccines. Patients were treated at Washington University (WashU) in St. Louis, MO and Duke University in Durham, NC. Each site’s respective institutional review board approved the study, with a data transfer agreement in place. RESULTS We identified 62 total (WashU=13; Duke=49) subjects with positive COVID-19 infection. Patients were predominantly white (85.5%), male (56.5%), with KPS &amp;gt;=70 (82.3%) and never smoked (69.4%). WashU patients tended to be older with grade 4 tumors, but this was not significant. At the time of COVID infection 35.5% of patients were receiving cancer-directed therapy. Notably, 37.1% experienced delayed care due to a COVID-19 diagnosis, most often for scheduled systemic treatment or radiation treatment. A further 37.1% had an ER visit, hospitalization, or ICU stay attributed to COVID-19. Of the 17 patients who died during the study period, 4 deaths were attributed directly to COVID-19 and not to their underlying brain tumor or other cause. Finally, telehealth use differed between sites (84.6% at WashU vs 14.3% at Duke). However, this difference could not be attributed to patient age, performance status, or distance from treating institution. CONCLUSION COVID-19 infection led to treatment delays and death for a subset, but not the majority of neuro-oncology patients. Telehealth use varied between sites and was not associated with commonly held assumptions about patient distance or performance status, suggesting evolving practice norms following telehealth’s introduction. Study limitations include a small sample size
MODL-36. EXPRESSION OF YAP1-MAML2 AND CONSTITUTIVELY ACTIVE YAP1 DRIVE THE FORMATION OF MENINGIOMA-LIKE TUMORS IN MICE THAT RESEMBLE NF2-MUTANT MENINGIOMAS
Authors: Frank Szulzewsky, Sonali Arora, Aleena Arakaki, Philipp Sievers, Damian Almiron Bonnin, Patrick Paddison, Felix Sahm, Patrick Cimino, Taranjit Gujral, Eric Holland
Journal: Neuro-Oncology (2022)

Abstract YAP1 is a transcriptional co-activator and oncogene under the control of the Hippo Signaling Pathway. Functional inactivation of Hippo Pathway tumor suppressors, including NF2, are frequent events in human cancers. Meningiomas are the most common primary brain tumors, and a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 gene copy, implicating oncogenic YAP activity in the pathobiology of almost half of these tumors. An alternate type of activating YAP1 mutation are YAP1 gene fusions that have been identified in several cancer subtypes. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2-wild type meningiomas. Here, we show that the expression profile of human YAP1-MAML2-positive pediatric meningiomas resembles that of the common NF2-mutant meningiomas based on global and YAP-related gene expression signatures. We then use the RCAS/tv-a system for postnatal gene transfer and show that the intracranial expression of YAP1-MAML2 in neonatal mice results in the formation of meningioma-like tumors that exert a similar gene expression pattern as seen in human YAP1 fusion-positive and NF2-mutant meningiomas and regulate classical YAP1 target genes. We demonstrate that YAP1-MAML2 exerts oncogenic YAP activity that is resistant to inhibitory Hippo pathway signaling and relies on the interaction with TEAD transcription factors. Pharmacological disruption of this interaction is sufficient to inhibit the viability of YAP1-MAML2-expressing mouse tumors ex vivo. Finally, we show that constitutively active YAP1 (S127/397A-YAP1) is also sufficient to cause the formation of similar meningioma-like tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a sufficient oncogenic driver in YAP1-MAML2 fusion-positive meningiomas, which mimic NF2-mutant meningiomas, and highlight TEAD-dependent YAP activity as a potential therapeutic target in these tumors.